title: Presenilin-1 regulates the expression of p62 to govern p62-dependent tau degradation.
abstract: Mutations in presenilin-1 (PS1) are tightly associated with early-onset familial Alzheimer's disease (FAD), which is characterized by extracellular amyloid plaques and the accumulation of intracellular Tau. In addition to being the catalytic subunit of γ-secretase, PS1 has been shown to regulate diverse cellular functions independent of its proteolytic activity. We found that cells deficient in PS1 exhibit reduced levels of p62 protein, a cargo-receptor shuttling Tau for degradation. The downregulation of PS1 led to a significant decrease in both the protein and mRNA transcript of p62, concomitant with attenuated p62 promoter activity. This PS1-dependent regulation of p62 expression was mediated through an Akt/AP-1 pathway independent of the proteolytic activity of PS1/γ-secretase. This p62-mediated Tau degradation was significantly impaired in PS1-deficient cells, which can be rescued by ectopic expression of either p62 or wild-type PS1 but not mutant PS1 containing FAD-linked mutations. Our study suggests a novel function for PS1 in modulating p62 expression to control the proteostasis of Tau.
authors.affiliation: Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, 128 Sec. 2 Academia Rd, Taipei, 11529, Taiwan.
authors.forename: Ying-Tsen
authors.initials: YT
authors.lastname: Tung
authors.forename: Bo-Jeng
authors.initials: BJ
authors.lastname: Wang
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.forename: Ming-Kuan
authors.initials: MK
authors.lastname: Hu
authors.forename: Guor Mour
authors.initials: GM
authors.lastname: Her
authors.forename: Wei-Pang
authors.initials: WP
authors.lastname: Huang
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D059748:Proteolysis; D000071456:Sequestosome-1 Protein; D015027:Zebrafish / Q000235:genetics; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C508853:PSEN1 protein, human; D053764:Presenilin-1; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D016875:tau Proteins